A Cross-Sectional Survey of Fixed-Dose Combination Antihypertensive Medicine Prescribing in Twenty-Four Countries, Including Qualitative Insights

Background: Treatment inertia, non-adherence and non-persistence to medical treatment contribute to poor blood pressure (BP) control worldwide. Fixed dose combination (FDC) antihypertensive medicines simplify prescribing patterns and improve adherence. The aim of this study was to identify factors associated with prescribing FDC antihypertensive medicines and to understand if these factors differ among doctors worldwide. Methods: A cross-sectional survey was conducted online from June 2023 to January 2024 to recruit doctors. We collaborated with an international network of researchers and clinicians identified through institutional connections. A passive snowballing recruitment strategy was employed, where network members forwarded the survey link to their clinical colleagues. The survey instrument, developed through a literature review, interviews with academic and clinical researchers, and pilot testing, assessed participants perspectives on prescribing FDC antihypertensive medicines for hypertension. Participants rated their level of agreement (5-point Likert scale) with statements representing six barriers and four facilitators to FDC use. Findings: Data from 191 surveys were available for analysis. 25% (n = 47) of participants worked in high-income countries, 38% (n = 73) in upper-middle income, 25% (n = 48) in lower-middle income, 6% (n = 10) in low-income countries. Forty percent (n = 70) of participants were between 36–45 years of age; two thirds were male. Cost was reported as a barrier to prescribing FDC antihypertensive medicines [51% (n = 87) agreeing or strongly agreeing], followed by doctors’ confidence in BP measured in clinic [40%, (n = 70)], access [37%, (n = 67)], appointment duration [35%, (n = 61)], concerns about side-effects [(21%, n = 37)], and non-adherence [12%, (n = 21)]. Facilitators to FDC antihypertensive polypills prescribing were clinician facing, such as access to educational supports [79%, (n = 143)], more BP measurement data [67%, (n = 120)], a clinical nudge in health records [61%, (n = 109)] and patient-facing including improved patient health literacy [49%, (n = 88)]. The levels of agreement and strong agreement across all barriers and facilitators were similar for participants working in higher or lower income countries. Across all countries, participants rated FDC antihypertensive medications highly valuable for managing patients with non-adherence, (82% reported high or very high value), for patients with high pill burden (80%). Interpretation: Cost and access were the most common barriers to prescribing FDCs across high- and low-income countries. While greater educational support for clinicians was perceived as the leading potential facilitator of FDC use, this seems unlikely to be effective without addressing access.


INTRODUCTION
Hypertension is the leading contributor to premature death globally (1), yet poorly controlled worldwide.In 2019, half of those with hypertension were aware of their condition, yet less than a quarter had their blood pressure (BP) controlled (2), with rates similar to a decade earlier (3).
Approximately 75% of hypertensive patients live in low-and middle-income countries where rates of awareness and control are particularly low (4).
Treatment inertia, the lack of up-titration of medications despite treatment targets not being reached is a major impediment to hypertension control (5)(6)(7) International studies report treatment inertia in as many as 60% of clinic visits where patients presented with uncontrolled BP in the United States (7), 58% of similar visits in Spain (8), and 65% of similar visits in the Dominican Republic (9).Treatment inertia is exacerbated in patients who require multiple medications to achieve targets, and when there are concerns regarding adverse events (10).Sub-optimal adherence and non-persistence also contribute to poor blood pressure control (11,12).A large meta-analysis of prospective epidemiologic studies linked up to 9% of cardiovascular disease events to poor adherence (13).Complex dosing regimens and polypharmacy are associated with non-adherence (14).
Fixed-dose combination (FDC) pills simplify treatment regimens (15) and have been shown in randomized clinical trials (RCTs) to improve adherence to BP-lowering therapy (16).There is also increasing research demonstrating safety and efficacy of triple and quadruple combination BPlowering FDC medicines (17).A recent exploratory analysis of the QUARTET RCT demonstrated that there was less treatment inertia among patients using the quad pill (FDC pill containing four ultra-low doses of BP-lowering drugs) compared to patients on monotherapy (18).Though this was different from an analysis of TRIUMPH, an unblinded RCT of low-dose triplecombination FDC, that observed higher treatment inertia rates among the intervention group (15).This discrepancy suggests that while FDC antihypertensive polypills offer a convenient and scalable management strategy, their impact on treatment inertia may vary across countries due to factors beyond medication characteristics.
The growing body of evidence on poor BP control, the need for combination BP lowering to achieve BP control, and the efficacy and safety of FDCs have led to recent updates to European guidelines on BP management, and the US Society of Hypertension recommend initial treatment with dual combination medicine (19,20).Yet the persisting lack of adoption of FDCs worldwide (3,(21)(22)(23) calls for further research into why FDCs are not utilized.The aim of this study was to identify factors associated with prescribing FDC antihypertensive medicines to patients with hypertension, and to understand if these factors differ among doctors working in low-, middle-or high-income countries.

STUDY DESIGN
This was a cross-sectional online global survey, whereby the countries in which the participants worked were categorized based on their World Bank classification at study initiation (24).The University of Sydney Human Research Ethics Committee (2023/362) approved the study.The trial protocol was registered on the Open Science Framework prior to recruitment (25).

SETTING AND PARTICIPANTS
The survey was created in Qualtrics™ (26) and distributed online using convenience nonprobability sampling.We collaborated with an international network of researchers, research clinicians and clinicians identified through institutional connections.We employed a passive snowballing recruitment strategy, whereby we encouraged members of this network to share the survey with their clinical colleagues, but we did not directly request the clinicians' contact details.The survey was open for six months between June-December 2023 and accessed via direct email.Recruitment efforts were supplemented with fortnightly updates to international collaborators to encourage continued promotion of the survey.Eligible participants were medical doctors, who as part of their usual medical practice prescribed antihypertensive medications to patients with high blood pressure.Participants from any country were eligible for inclusion.

SURVEY INSTRUMENT
The survey instrument was developed in an iterative process with members of the research team, including academic and clinical researchers.We conducted a literature review to inform the possible barriers and facilitators to polypill prescribing internationally (27)(28)(29).We then developed an initial draft of the survey, using established design principles (30,31).Subsequently, we conducted an interview with prescribing doctors and members of our research team (family physician [TU], cardiologist [CK], and gerontologist [TN]), to further refine items to assure content validity and wording clarity.The survey was pilot tested on a group of participants who were representative of the target population (n = 16).The feedback received was analyzed and the survey was refined.Due to the known challenges of recruiting doctors to complete surveys (32)(33)(34), the survey was optimized for brevity and ease of completion.The final version was pilot tested again with clinicians prior to commencing recruitment.The full survey is available in Supplementary Material 2. We commenced recruitment using an English language version of the survey and translated the survey into the six UN languages (English, French, Arabic, Russian, Chinese, Spanish) to enable international recruitment.The survey was translated using backtranslation, whereby the original survey was translated to one of the six languages by a native speaker and the translation back translated into English (35).

VARIABLES
In this study, fixed-dose combination referred to single-pill combination medicines, where two or more antihypertensive medicines were combined.Participants rated their agreement (5-point scale, with a range from 0 indicating strong disagreement to 5 indicating strong agreement) with six statements to represent barriers and four statements to represent facilitators to FDC antihypertensive medicine prescribing for patients with hypertension.Demographic characteristics, geographic location, clinical experience, and current prescribing practices, including frequency of prescribing FDC medicines for the last 10 patients treated with hypertension were self-reported.Additionally, participants rated the value of a FDC antihypertensive medicine in various clinical scenarios (5-point scale: 1-very low value, 5 = high value) and importance of different factors influencing their decision to initiate FDC antihypertensive therapy (5-point scale: 1 = not at all important, 5 = extremely important).
Finally, an open-ended question invited participants to share additional comments on barriers and facilitators to FDC antihypertensive medicine use for the control of hypertension.

DATA ANALYSIS
Continuous variables are presented through centrality measures (mean, median), and dispersion (SD and IQR) according to the distribution, and categorical variables through frequencies and percentages.Data from physicians who work in high-income countries and upper-middleincome countries were combined, lower-middle-income countries and low-income countries were combined to create a higher income and lower income groups (36).Having two broader groups (high and low) enhanced statistical power while capturing significant variations in socioeconomic contexts.
The median and IQR score for agreement with each barrier and facilitator is presented.We calculated the standardized mean difference in scores between participants from higher-income countries or lower-income countries.These results are presented along with the corresponding confidence intervals.We examined the relationship between FDC prescribing frequency and selfreported barriers and facilitators to FDC use.We examined whether this relationship varied by whether the participant worked in a higher or lower income country using interaction analysis.The value of FDC antihypertensive medication and considerations for initiating such therapy in hypothetical clinical scenarios were described and presented as proportions.Analysis was performed in the R environment for statistical computing, version 4.3.2(37).
One researcher (EO) performed a thematic analysis on the responses to the open-ended question to understand participants' perspective and interpreted the comments alongside the demographic, clinical and prescribing practices data.The interpretation was reviewed by another author (DM).

ROLE OF THE FUNDING SOURCE
This research did not receive any external funding or financial support from any organization or institution.

RESULTS
Between June 2023 and January 2024, we recruited registered doctors who prescribed BPlowering medicines.The participants trained in 32 different countries and work in 24 different countries.Of the countries where the participants work, 21 of the countries were higherincome, and 11 were lower-income countries.
We had complete data from 191 surveys in total and missing data across 48 surveys.Figure 1 shows the numbers of participants analyzed for each block of survey questions: 25% (n = 47) of participants worked in high income countries, 38% (n = 73) worked in upper-middle income countries, 25% (n = 48) worked in lower-middle income countries, 6% (n = 10) worked in lowincome countries, and 6% (n = 12) did not complete that question in the survey.Figure 2 shows a world map with the countries that were represented in the survey; a full list is available in Supplementary Material 3, Table 1.
Cost was the most commonly selected barrier to prescribing FDC (n = 87, 51%, agreed or strongly agreed) followed by confidence in clinic BP measurement (n = 70, 40% agreed or strongly agreed), access to FDC medicines (n = 67, 37% agreed or strongly agreed), appointment duration (n = 61, 35% agreed or strongly agreed), patient concerns about side-effects (n = 37, 21% agreed or strongly agreed) and concerns about patient non-adherence (n = 21, 12% agreed or strongly agreed).The levels of agreement and strong agreement across all barriers were the same for participants working in higher or lower income countries, with no difference between groups.These results are presented in Table 2 and Supplementary Material 4, Figure 1.
Access to educational supports such as feedback on prescribing patterns compared with peers was the most commonly selected facilitator to prescribing FDC (n = 143, 79% agreed or strongly agreed), followed by more BP measurement data (n = 120, 67% agreed or strongly agreed), a clinical nudge or prompt in a health record (n = 109, 61% agreed or strongly agreed), and improved patient health literacy (n = 88, 49% agreed or strongly agreed).The levels of agreement and strong agreement across all facilitators were the same for participants working in higher-or lower-income countries, with no difference between groups.These results are presented in Table 2 and Supplementary Material 4, Figure 1.
Both reported access and reported cost as barriers to prescribing FDCs were significantly associated with a lower prescription of FDC [access: β 0.58 (95% CI -0.86 to -0.29); cost β -0.81 (95% CI -1.14 to -0.50)].Other investigated barriers or facilitators were not associated with prescription of FDC.There were no significant interactions with country income level of clinician (Table 3).Most participants were from Australia (n = 22), India (n = 34), or Malaysia (n = 64).We described the response of participants from these three countries to each barrier and facilitator and noted differences between Australia and Malaysia.In Australia 5% (n = 1) agreed or strongly agreed that access is a barrier to FDC antihypertensive medicines in comparison to 52% (n = 33) in Malaysia, similarly in relation to cost in Australia 14% (n = 3) agreed or strongly agreed that cost was a barrier whereas in Malaysia this was 70% (n = 45).These results are available in Supplementary Material 5.
Across all countries, participants rated FDC antihypertensive medications highly valuable for managing patients with non-adherence (82% reported high or very high value), for patients with high pill burden (80%).The proportion reporting highly valuable trended down across the   3 and Supplementary Material 5, Table 2.
There were open-ended question responses from 143 participants to the question, 'What additional comments do you have regarding barriers and facilitators to the use of fixed-dose combination antihypertensive medications for the control of hypertension?'The responses were distilled and organized into themes with quotes abstracted from the data.The quotes are presented with the participants country of practice, age range, and clinical speciality.

THEME 1: RESOURCE DEPENDENT
This theme incorporated the subthemes of cost and availability.The expense of antihypertensive medications was cited as a prohibitive barrier.This is interpreted from the quotes below.Availability was also identified as a barrier.This is interpreted from the quote below.
There is need for widely available generic fixed dose combinations (StudyID 148, Upper-middle-income country (Jamaica), 46-55 years old, Internal Medicine) Commonly cost and availability were reported together as barriers.
Main barrier in my working place would be cost and availability of FDC….(StudyID 128, Upper-middle-income country (Malaysia), 26-35 years old, General Medicine) Financial burden is one of the most important factors in prescription of medications in government settings.Patients wants to take fixed drug combinations, but they want medications free from hospital pharmacy where limited single drugs are available, limiting intake of field drug combinations (StudyID 116, Lower-middleincome country (India), 26-35 years old, Geriatrician)

THEME 2: CHALLENGES OF A FIXED DOSE
This theme incorporated the subthemes of concerns regarding dosage control and concerns regarding patient perceptions of fixed doses.A challenge with prescribing fixed-dose combinations is that doctors lose control over the dosage of each medicine.This theme was interpreted from the quotes below.
Prescribers are often concerned about side effects as there are not as many steps up or down in terms of dosages (StudyID 1, High-income country (St.Kitts and Nevis), 45-55 years old, Cardiologist) Barrier to fixed-drug combo is when GP wants to add a second agent but the first anti-hypertensive and preferred second agent are not available in fixed-dose combo (StudyID 3, High-income country (Australia), 36-45 years old, Family Practitioner) Difficulties with dose adjustment with fixed-dose antihypertensive medications (StudyID 148 Upper-middle-income country (Malaysia), 46-55 years old, Family Practitioner) A participant reported on the challenge of managing patient expectations when prescribing medicines as a fixed dose.
Barrier would be patient perceptions on giving both medications without been able to adjust the dose (StudyID 136, Upper-middle-income country (Malaysia), 26-35 years old, General Medicine)

THEME 3: INSUFFICIENT INFORMATION
This theme incorporated the subthemes of concerns regarding side effects and insufficient education on fixed doses.Participants reported on fear of side effects, and difficulty determining which component is causing them.This theme was interpreted form the quotes below.

Figure 1
Figure 1 Number of participants who completed each block of survey questions.

Figure 3
Figure 3 Value placed on fixed-dose combination antihypertensive medication in clinical scenarios.

Figure 4
Figure 4 Factors important in the decision to initiate fixeddose combination medicines.
my concern is with side effects, a combination gives twice the opportunity to have side effects (StudyID 121, High-income country (New Zealand), 56-65 years old, Family Practitioner) Other participants reported that they hadn't sufficient guidance on when and how to use FDC medicines.patient profile i.e. elderly, try not to use FDC (StudyID 20, Upper-middle-income country (Malaysia), 36-45 years old, Family Practitioner) Information about misconception of long-term side effects on organ damage is lacking among our patients (StudyID 19, Upper-middle-income country (Malaysia), 36-45 years old, Family Practitioner) One specifically recommended the following: Physician education and product brochures (StudyID 10, Upper-middle-income country (Malaysia), 46-55 years old, Cardiologist)

Table 1
Participant characteristics, clinical experience, and prescribing patterns.

Table 2
Barriers and facilitators to prescribing for doctors in high-and upper-middle income or lower-middle and low-income countries.